One of our objectives in this study was to investigate the potential involvement of SOCS1 in pathways that regulate the severity of ocular HSV-1 infection or endotoxin-induced uveitis (EIU), a mouse model of human anterior uveitis. We also sought to genetically engineer cell-penetrating SOCS1 and SOCS3 (CP-SOCS1 and CP-SOCS3) for use in delivering SOCS proteins into cells. We used transgenic rats that over-express SOCS1 in the retina and mice with targeted deletion of SOCS1 in the retina in these studies. Our data revealed that SOCS1 promotes HSV-1 replication by inhibiting immune responses to HSV-1 during ocular HSV-1 infection, suggesting that topical SOCS1 antagonists can be useful in suppressing ocular HSV-1 infection and mitigating herpetic stromal keratitis. On the other hand, EIU is more severe in SOCS1-deficient mice and correlated with elevated levels of chemokines/chemokine receptors and expansion of pathogenic Th17 cells, suggesting that therapeutic delivery of SOCS proteins into ocular or inflammatory cells can be employed to confer protection against anterior uveitis. In proof-of-principle studies we demonstrate the inhibition of IL-6/STAT3 and IFNg/STAT1 signaling and suppression of pathogenic Th17 cells by CP-SOCS3 and CP-SOCS1 proteins, respectively. The efficacy of the CP-SOCS proteins in inhibiting pro-inflammatory pathways and Th17 cells has thus laid the foundation for therapeutic use of CP-SOCS in uveitis.